Evidence Synthesis Number 74 _ Screening for Breast Cancer: Systematic Evidence Review Update for the U S Preventive Services Task Force Prepared For: Agency for Healthcare Research and Quality U.S Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract Number 290-02-0024, Task Order Number Prepared By: Oregon Evidence-based Practice Center Oregon Health & Science University 3181 SW Sam Jackson Park Rd Portland, Oregon 97239 www.ohsu.edu/epc/usptf/index.htm Investigators: Heidi D Nelson MD, MPH Kari Tyne, MD Arpana Naik, MD Christina Bougatsos, BS Benjamin Chan, MS Peggy Nygren, MA Linda Humphrey MD, MPH AHRQ Publication No 10-05142-EF-1 November 2009 This report is based on research conducted by the Oregon Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No 290-02-0024) The investigators involved have declared no conflicts of interest with objectively conducting this research The findings and conclusions in this document are those of the authors, who are responsible for its content, and not necessarily represent the views of AHRQ No statement in this report should be construed as an official position of AHRQ or of the U.S Department of Health and Human Services The information in this report is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services This report is intended as a reference and not as a substitute for clinical judgment This report may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies AHRQ or U.S Department of Health and Human Services endorsement of such derivative products may not be stated or implied Acknowledgements This project was funded by AHRQ for the U.S Preventive Services Task Force (USPSTF) Additional support was provided by the Veteran’s Administration Women’s Health Fellowship (Dr Tyne) and the Oregon Health & Science University Department of Surgery in conjunction with the Human Investigators Program (Dr Naik) Data collection for some of this work was supported by the NCI-funded Breast Cancer Surveillance Consortium (BCSC) cooperative agreement (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040) The collection of cancer incidence data used in this study was supported in part by several state public health departments and cancer registries throughout the United States A full description of these sources is available at http://breastscreening.cancer.gov/work/acknowledgement.html The authors acknowledge the contributions of the AHRQ Project Officer, Mary Barton, MD, MPP, and USPSTF Leads Russ Harris, MD, MPH; Allen Dietrich, MD; Carol Loveland-Cherry, PhD, RN; Judith Ockene, PhD, MEd; and Bernadette Melnyk, PhD, RN, CPNP/NPP Andrew Hamilton, MLS, MS, conducted the literature searches and Sarah Baird, MS, managed the bibliography at the Oregon EPC The authors thank the BCSC investigators, participating mammography facilities, and radiologists for the data used in this project A list of the BCSC investigators and procedures for requesting BCSC data for research purposes are available at http://breastscreening.cancer.gov/ The authors also thank Patricia A Carney, PhD; Steve Taplin, MD; Sebastien Haneuse, PhD; and Rod Walker, MS, for their direct work with this project Suggested Citation: Nelson HD, Tyne K, Naik A, Bougatsos C, Chan B, Nygren P, Humphrey L Screening for Breast Cancer: Systematic Evidence Review Update for the U.S Preventive Services Task Force Evidence Review Update No 74 AHRQ Publication No 10-05142-EF-1 Rockville, MD: Agency for Healthcare Research and Quality; 2009 Breast Cancer Screening ii Oregon Evidence-based Practice Center Structured Abstract Background: This systematic review is an update of new evidence since the 2002 U.S Preventive Services Task Force recommendation on breast cancer screening Purpose: To determine the effectiveness of mammography screening in decreasing breast cancer mortality among average-risk women age 40-49 years and 70 years and older; the effectiveness of clinical breast examination (CBE) and breast self examination (BSE) in decreasing breast cancer mortality among women of any age; and harms of screening with mammography, CBE, and BSE Data Sources: The Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2008), MEDLINE® searches (January 2001 to December 2008), reference lists, and Web of Science® searches for published studies and Breast Cancer Surveillance Consortium for screening mammography data Study Selection: Randomized, controlled trials with breast cancer mortality outcomes for screening effectiveness, and studies of various designs and multiple data sources for harms Data Extraction: Relevant data were abstracted, and study quality was rated by using established criteria Data Synthesis: Mammography screening reduces breast cancer mortality by 15% for women age 39-49 (relative risk [RR] 0.85; 95% credible interval [CrI], 0.75-0.96; trials) Results are similar to those for women age 50-59 years (RR 0.86; 95% CrI, 0.75-0.99; trials), but effects are less than for women age 60-69 years (RR 0.68; 95% CrI, 0.54-0.87; trials) Data are lacking for women age 70 years and older Radiation exposure from mammography is low Patient adverse experiences are common and transient and not affect screening practices Estimates of overdiagnosis vary from 1-10% Younger women have more false-positive mammography results and additional imaging but fewer biopsies than older women Trials of CBE are ongoing; trials of BSE showed no reductions in mortality but increases in benign biopsy results Limitations: Studies of older women, digital mammography, and magnetic resonance imaging are lacking Conclusions: Mammography screening reduces breast cancer mortality for women age 39-69 years; data are insufficient for women age 70 years and older False-positive mammography results and additional imaging are common No benefit has been shown for CBE or BSE Breast Cancer Screening iii Oregon Evidence-based Practice Center Table of Contents Chapter Introduction Purpose of Review and Prior USPSTF Recommendation Condition Definition Prevalence and Burden of Disease .2 Etiology and Natural History .3 Risk Factors Current Clinical Practice Screening Diagnosis Treatment .6 Screening Recommendations of Other Groups Mammography .7 Clinical Breast Examination Breast Self Examination Chapter Methods Key Questions and Analytic Framework Search Strategies Study Selection Data Abstraction and Quality Rating Meta-analysis of Mammography Trials .10 Analysis of Breast Cancer Surveillance Consortium Data 10 External Review 11 Chapter Results .11 Key Question 1a Does screening with mammography (film and digital) or MRI decrease breast cancer mortality among women age 40-49 years and 70 years and older? 11 Summary 11 Detailed Findings 12 Meta-analysis for women age 39-49 years 13 Results for women age 70-74 years 13 Comparisons with meta-analyses for women age 50-59 years and 60-69 years .13 Key Question 1b Does CBE screening decrease breast cancer mortality? Alone or with mammography? .14 Summary 14 Detailed Findings 14 Key Question 1c Does BSE practice decrease breast cancer mortality? 16 Summary 16 Detailed Findings 16 Key Question 2a What are the harms associated with screening with mammography (film and digital) and MRI? .17 MRI and Digital Mammography 17 Radiation Exposure 17 Breast Cancer Screening iv Oregon Evidence-based Practice Center Pain During Procedures 18 Anxiety, Distress, and Other Psychological Responses .19 False-positive and False-negative Mammography Results, Additional Imaging, and Biopsies 19 Overdiagnosis 20 Key Question 2b What are the harms associated with CBE? 22 Key Question 2c What are the harms associated with BSE? 22 Chapter Discussion 23 Summary .23 Limitations 24 Future Research 25 Conclusions 25 References 26 Figures Figure Analytic Framework and Key Questions Figure Pooled Relative Risk for Breast Cancer Mortality from Mammography Screening Trials for Women Age 39 to 49 Years Figure Number of Women Undergoing Routine Mammography to Diagnose Case of Invasive Cancer, DCIS, or Either in the Breast Cancer Surveillance Consortium Figure Number of Women Undergoing Additional Imaging and Number Undergoing Biopsy to Diagnose Case of Invasive Cancer the Breast Cancer Surveillance Consortium Tables Table Breast Cancer Screening Recommendations for Average-Risk Women Table Mammography Screening Trials Included in Meta-analyses Table Sensitivity Analysis: Meta-analysis of Screening Trials of Women Age 39 to 49 Years Table Summary of Screening Trials of Women Age 70 to 74 Years Table Pooled Relative Risk for Breast Cancer Mortality from Mammography Screening Trials for All Ages Table Trials of Clinical Breast Examination and Breast Self Examination Table Age-specific Screening Results from the Breast Cancer Surveillance Consortium Table Studies of Breast Cancer Overdiagnosis Table Summary of Evidence Appendices Appendix A1 Acronyms and Abbreviations Appendix B Detailed Methods Appendix B1 Literature Search Strategies Breast Cancer Screening v Oregon Evidence-based Practice Center Appendix B2 Search Results by Key Question Appendix B3 List of Excluded Studies Appendix B4 U.S Preventive Services Task Force Quality Rating Methodology for Randomized Controlled Trials and Observational Studies Appendix B5 Quality Rating Methodology for Systematic Reviews Appendix B6 Details of the Meta-analysis Appendix B7 Breast Cancer Surveillance Consortium Methods Appendix B8 Expert Reviewers of the Draft Report Appendix C Other Results Appendix C1 Contextual Question: What is the cost-effectiveness of screening? Appendix C2 Statistical Tests for Meta-analysis and Screening Trials of Women Age 39 to 49 Years Breast Cancer Screening vi Oregon Evidence-based Practice Center CHAPTER INTRODUCTION Purpose of Review and Prior USPSTF Recommendation This systematic evidence review is prepared for the U.S Preventive Services Task Force (USPSTF) to update its previous recommendation on breast cancer screening for average-risk women.1 In 2002, based on results of a systematic evidence review,2, the USPSTF recommended screening mammography, with or without clinical breast examination (CBE), every 1-2 years for women age 40 years and older The USPSTF concluded that the evidence was insufficient to recommend for or against routine CBE alone to screen for breast cancer The USPSTF also concluded that the evidence was insufficient to recommend for or against teaching or performing routine breast self examination (BSE) (See Appendix A1 for abbreviations.) The USPSTF made additional conclusions about the state of the evidence in 2002 including: • The relative risk of breast cancer death for women randomized to mammography screening versus no mammography screening based on a meta-analysis of trials was 0.84 (95% credible interval [CrI], 0.77-0.91) • Older women have a higher risk of developing and dying from breast cancer, but they also have a higher chance of dying from other causes • Reductions in breast cancer mortality in studies using mammography alone versus studies using mammography and CBE are comparable There is no direct evidence that CBE or BSE decreases mortality • Mammography sensitivity and specificity are higher than CBE sensitivity and specificity (77-95% and 94-97% versus 40-69% and 88-99%, respectively) • The positive predictive value of mammography increases with age and with a family history of breast cancer • The benefit of regular mammography increases with age, while harms from mammography decrease with age However, the age at which the benefits outweigh the harms is subjective Biennial mammography is as effective as annual mammography for women age 50 years or older Breast cancer progresses more rapidly in women younger than 50, and sensitivity of mammography is lower in this group A clear advantage of annual mammography screening for women in this age group was not found • The majority of abnormal mammography examinations or CBEs are false-positives Screening may increase the number of women undergoing treatment for lesions that might not pose a threat to their health Several evidence gaps were identified including: • Definitive estimates of the proportion of benefits due to screening before age 50 years cannot be made The cost-effectiveness of screening women younger than age 50 years is unknown • The age at which it is appropriate to cease breast cancer screening is unknown, as are the benefits of screening women older than 69 years Breast Cancer Screening Oregon Evidence-based Practice Center • • • No screening trial has examined the benefits of CBE alone compared to no screening The benefits of CBE as well as possible benefits of BSE are unknown The magnitude of the harms associated with all methods and ages is unclear None of the trials conducted to date has directly addressed the issue of the appropriate screening interval among any age group This update focuses on critical evidence gaps that were unresolved at the time of the 2002 recommendation, including the effectiveness of mammography in decreasing breast cancer mortality among average-risk women age 40-49 years and 70 years and older; the effectiveness of CBE and BSE in decreasing breast cancer mortality among women of any age; and harms of screening with mammography, CBE, and BSE Studies of the cost-effectiveness of screening are described in the Appendix Performance characteristics of screening methods (e.g., sensitivity and specificity) were previously reviewed and are not included in this update Condition Definition Breast cancer is a proliferation of malignant cells that arises in the breast tissue, specifically in the terminal ductal-lobular unit The term “breast cancer” represents a continuum of disease, ranging from noninvasive to invasive carcinoma.4 Screening techniques may detect any of these disease entities as well as noncancerous lesions such as benign breast cysts Noninvasive carcinoma consists of epithelial proliferation confined to either the mammary duct, as with ductal carcinoma in situ (DCIS), or to the lobule, as with lobular carcinoma in situ (LCIS) Because noninvasive or in situ lesions not invade the surrounding stroma, they cannot metastasize LCIS is generally not considered a precursor lesion for invasive lobular carcinoma, but believed to be a marker for increased risk of invasive ductal or lobular breast cancer development in either breast.5 However, DCIS is thought to be a precursor lesion to invasive ductal carcinoma DCIS consists of a heterogeneous group of lesions with varying clinical behavior and pathologic characteristics Common subtypes of DCIS include cribriform, comedo, micropapillary, papillary, and solid.6 Unlike noninvasive lesions, invasive breast cancers invade the basement membrane into the adjacent stroma, and therefore, have metastatic potential The most common sites of metastasis include adjacent lymph nodes, lung, brain, and bone.4 Approximately 70-80% of invasive breast cancers are invasive or infiltrating ductal carcinoma and approximately 10% are invasive lobular cancers.4 Some other less common histologic subtypes of invasive breast cancer include apocrine, medullary, metaplastic, mucinous, papillary, and tubular.4 Prevalence and Burden of Disease Breast cancer is the most frequently diagnosed non-cutaneous cancer and the second leading cause of cancer deaths after lung cancer among women in the United States.7 In 2008, an Breast Cancer Screening Oregon Evidence-based Practice Center estimated 182,460 cases of invasive and 67,770 cases of noninvasive breast cancer were diagnosed, and 40,480 women died of breast cancer.8 The incidence of breast cancer increases with age Based on Surveillance Epidemiology and End Results (SEER) data from 2002-2004, the National Cancer Institute (NCI) estimates that 14.7% of women born in the United States today will develop breast cancer in their lifetimes, 12.3% with invasive disease.9 The probability of a woman developing breast cancer in her forties is in 69, in her fifties in 38, and in her sixties in 27.10 Although the incidence rate of breast cancer has increased since the 1970s and 1980s, recent data suggest that it may have stabilized between 2001-2003 Overall, the incidence rate declined by 6.7% between 2002-2003 from 137.3 to 124.2 per 100,000 women.11 Age-adjusted incidence rates for breast cancer also declined each year during 1999-2003.12 This trend may be attributed to discontinuation of menopausal hormone therapy,11, 13 and a plateau or decline in use of screening mammography.14 Breast cancer mortality has decreased since 1990 at a rate of 2.3% per year overall.15, 16 Women age 40-50 years had a decline in breast cancer mortality of 3.3% per year An evaluation of mortality trends from 1990 through 2000 from studies attributed 28-65% of the decline to mammography screening, while the remainder of the decline was due to improved adjuvant treatments.17 Etiology and Natural History The etiology of breast cancer is still largely unknown, although it is believed that breast cancer development is due to aberrations in cell cycle regulation Current research focuses on clarifying the role of both inherited and acquired mutations in oncogenes and tumor suppressor genes and the consequences these mutations may have on the cell cycle, as well as investigating various prognostic biological markers The contribution external influences, such as environmental exposures, may have on regulatory genes is unclear Currently, no single environmental or dietary exposure has been found to cause a specific genetic mutation that causes breast cancer Lifetime exposure to both endogenous and exogenous hormones has been hypothesized to play a role in tumorigenesis and growth Other potential causes of breast cancer include inflammation and virally mediated carcinogenesis.18 The significance of DCIS as a precursor lesion is unclear With the widespread use of screening mammography in the United States, nearly 90% of DCIS cases are now diagnosed only on imaging studies, most commonly by the presence of microcalcifications These represent approximately 23% of all breast cancer cases (not including LCIS).7 Although it is the most common type of noninvasive breast cancer, its natural history is poorly understood Whether DCIS in an obligate precursor to invasive ductal cancer, or if both entities derive from a common progenitor cell line is unclear While some evidence suggests that DCIS and invasive ductal cancer may diverge from common progenitor cells,19 indirect evidence supports the theory of linear progression through stages, from atypical hyperplasia to DCIS to invasive cancer.19 Further evidence supports a hybrid of these two theories Through an accumulation of genetic changes, atypical hyperplasia progresses to low grade DCIS, followed by high grade DCIS, and Breast Cancer Screening Oregon Evidence-based Practice Center from any point in this progression, the step to invasive cancer occurs.20 Consistent with all three theories is evidence from studies in which DCIS coexists with adjacent invasive cancer in pathology specimens, as well as studies showing that at least 50% of local recurrences after treatment for DCIS are invasive cancers.21 In both cases, DCIS and invasive ductal cancer breast tissues frequently share morphological and molecular characteristics, including grade and estrogen receptor status and HER2/neu oncogene expression.21-23 Several recent reviews include older studies of untreated DCIS cases that were diagnosed on retrospective review of previously reported benign biopsy specimens.21, 24, 25 In these studies, untreated DCIS progressed to invasive cancer in 14-53% of cases over mean periods of 8-22 years In a case series of 775 women diagnosed with DCIS who underwent breast conserving therapy, 66 eventually developed invasive cancer, and 71 developed recurrent DCIS at a mean follow-up of 5.4 years.26 Risk Factors Although several risk factors have been associated with breast cancer, most cases occur in women with no specific risk factors other than sex and age Family history of breast and ovarian cancer are strong risk determinants however, with the number of relatives, closeness of the degree of relationships, and ages of diagnosis of affected family members contributing For example, two or more relatives with breast or ovarian cancer, a relative with both breast and ovarian cancer, and a relative diagnosed younger than age 50 years all substantially increase risk.27 Hereditary mutations in tumor suppressor genes BRCA1 and BRCA2 increase individual risks for breast cancer 60-85% and may be identified in 5-10% of all breast cancer cases.28 Personal history of noninvasive breast cancer or previous abnormal breast biopsy containing LCIS or atypical ductal or lobular hyperplasia increase risk for invasive breast cancer Extensive mammographic breast density is also associated with increased risk of breast cancer.29 Endogenous estrogen exposure is associated with increased risk; thus early menarche, late menopause, nulliparity, and obesity are implicated as risk factors Use of combination postmenopausal hormone therapy (estrogen and progestin) was associated with an increased relative risk for breast cancer compared to placebo in the Women’s Health Initiative (WHI) randomized controlled trial.30 Environmental exposures are believed to increase risk A history of chest radiation therapy, such as treatment for Hodgkin lymphoma, increases the risk for developing breast cancer.31 However, current approaches may not pose this same magnitude of risk.31 Use of alcohol at levels more than 1-2 drinks per day is also associated with increased breast cancer.30 Empiric models have been developed in attempts to predict risk of developing cancer for individual women (e.g., BRCAPRO, Gail, Claus, and Tyrer-Cuzick).27 All of these models incorporate age and number of first-degree relatives with breast cancer into their calculations, but vary in their complexity However, these models have been shown to perform better in predicting population risk than in predicting an individual’s risk and it is unclear how to apply these models to screening.27 Breast Cancer Screening Oregon Evidence-based Practice Center Appendix B4 U.S Preventive Services Task Force Quality Rating Methodology for Randomized Controlled Trials and Observational Studies1 Randomized Controlled Trials (RCTs) and Cohort Studies Criteria: • Initial assembly of comparable groups: RCTs—adequate randomization, including concealment and whether potential confounders were distributed equally among groups; cohort studies—consideration of potential confounders with either restriction or measurement for adjustment in the analysis; consideration of inception cohorts • Maintenance of comparable groups (includes attrition, cross-overs, adherence, contamination) • Important differential loss to follow-up or overall high loss to follow-up • Measurements: equal, reliable, and valid (includes masking of outcome assessment) • Clear definition of interventions • Important outcomes considered • Analysis: adjustment for potential confounders for cohort studies, or intension-to-treat analysis for RCTs Definition of ratings based on above criteria: Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study (follow-up at least 80 percent); reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; important outcomes are considered; and appropriate attention to confounders in analysis Fair: Studies will be graded “fair” if any or all of the following problems occur, without the important limitations noted in the “poor” category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred in follow-up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are accounted for Poor: Studies will be graded “poor” if any of the following major limitations exists: Groups assembled initially are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied at all equally among groups (including not masking outcome assessment); and key confounders are given little or no attention Case Control Studies Criteria: • Accurate ascertainment of cases • Nonbiased selection of cases/controls with exclusion criteria applied equally to both • Response rate • Diagnostic testing procedures applied equally to each group • Measurement of exposure accurate and applied equally to each group • Appropriate attention to potential confounding variable Breast Cancer Screening 75 Oregon Evidence-based Practice Center Appendix B4 U.S Preventive Services Task Force Quality Rating Methodology for Randomized Controlled Trials and Observational Studies1 Definition of ratings based on criteria above: Good: Appropriate ascertainment of cases and nonbiased selection of case and control participants; exclusion criteria applied equally to cases and controls; response rate equal to or greater than 80 percent; diagnostic procedures and measurements accurate and applied equally to cases and controls; and appropriate attention to confounding variables Fair: Recent, relevant, without major apparent selection or diagnostic work-up bias but with response rate less than 80 percent or attention to some but not all important confounding variables Poor: Major selection or diagnostic work-up biases, response rates less than 50 percent, or inattention to confounding variables REFERENCE Harris RP, Helfand M, Woolf SH, et al Current Methods of the U.S Preventive Services Task Force: a review of the process Am J Prev Med 2001;20(3Suppl):21-35 Breast Cancer Screening 76 Oregon Evidence-based Practice Center Appendix B5 Quality Rating Methodology for Systematic Reviews1-3 Comprehensiveness of sources/search strategy used: a Were search terms reported? b Was the search comprehensive (Medline, search reference lists and/ or experts)? c Were the search terms applicable? Standard appraisal of included studies: a Were inclusion/exclusion criteria reported? b Are criteria valid? Quality/validity assessment: a Were criteria for validity/quality assessment explicit and applied to all studies? b Were quality criteria appropriate (e.g criteria appropriate for study design)? Analysis/synthesis: a Were methods used to combine studies reported? b Were studies that were combined similar to one another (e.g appropriate to combine, similar patient populations etc)? Validity of conclusions: a Were conclusions supported by the data? Recency and relevance: a Is the study recent and relevant to scope? REFERENCES Harris RP, Helfand M, Woolf SH, et al Current methods of the U.S Preventive Services Task Force: a review of the process Am J Prev Med 2001;20(3Suppl):21-35 National Institute for Health and Clinical Excellence The Guidelines Manual London: Institute for Health and Clinical Excellence; 2006 Oxman AD, Guyatt GH Validation of an index of the quality of review articles J Clin Epidemiol 1991;44:1271-8 Breast Cancer Screening 77 Oregon Evidence-based Practice Center Appendix B6 Details of the Meta-analysis The meta-analysis is an update of the previous 2002 meta-analysis that includes results from published trials of mammography screening for women age 39-49 years reporting reduction in breast cancer mortality With the addition of only new data point, the meta-analysis for the update was less extensive than the 2002 meta-analysis We did not update the model for relative risk and length of follow-up (the two-level hierarchical model) We conducted similar updates for other age groups for context As with the original 2002 meta-analysis, we estimated the model by using a Bayesian data analytic framework but this time using the BRugs package in R.1,2 BRugs is an R interface to OpenBUGS, the successor to WinBUGS The R code to create the dataset is below # R code to create dataset study